Because abuse and associated problems of the phenylethylamine drugs, such as methamphetamine (METH), continue to be a major concern in the United States and throughout the world, it is critical to under- stand the short- and long-term consequences resulting from abusing these psychostimulants. Of particular relevance to this project is the elucidation of the role of monoamine transporters to the acute andchronic effects of phenylethylamines. We recently demonstrated that METH treatments rapidly and profoundly reduce the activity of vesicular monoamine transporters-2 (VMAT-2) in striatal purified vesicles. This VMAT- 2 Acute Transporter Response (VATR) has at least two distinct components: one (1st component) that occurs after a single METH administration, and the other (2nd component) apparently only after multiple METH adminstrations that lead to neurotoxicity. Based on these observations, we hypothesize that "Expression of a 2nd, but not the 1st, component of the VATR is linked to occurrence of phenylethylamine- induced monoamine neurotoxicity." This hypothesis will be tested by achieving the following Specific Aims: A. Determine and compare the features of the components of the METH-induced striatal VATR. We will study and contrast the full complement of basic dose, temporal, kinetic, anatomical, and mechanistic features of the VATR after a single (nontoxic) and multiple (neurotoxic) METH administrations. B. Elucidate the funtional significance of the VATR components. This will be accomplished by determining if the VATR components interfere with vesicular monoamine sequestration and releasing functions. C. Determine the effects on VATR expression of diverse phenylethylamines (i.e., amphetamine, MDMA, fenfluramine, and ephedrine), with monoamine neurotoxcity profiles distinct from METH. This will identify how the VATR components link with the various effects on monoamine systems and different expressions of monoamine toxicity associated with these distinct phenylethylamine analogs.